The role of H3K27 acetylation in oxygen-glucose deprivation-induced spinal cord injury and potential for neuroprotective therapies

IF 3.5 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-01-01 DOI:10.1016/j.brainresbull.2024.111152

Jing Wang , Zheng Guan , Weina Li , Yu Gong , Heying Wang , Ting Zhou , Jingjie Liu

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引用次数: 0

Abstract

Objective

Spinal cord injury (SCI) is a debilitating condition that often results in paralysis and lifelong medical challenges. Research has shown that epigenetic modifications, particularly histone acetylation, play a role in neuroprotection following hypoxic-ischemic events in SCI. The objective of this study was to explore the effects of histone H3K27 acetylation, along with its underlying mechanisms, on the tolerance to hypoxia and ischemia in SCI.

Methods

This study employed an organotypic spinal cord slice culture model subjected to oxygen-glucose deprivation (OGD). We assessed cell apoptosis and changes in cellular type patterns under these conditions. Following hypoxia and ischemia, we analyzed the expression and distribution of H3K27ac across various nerve cell types. To identify key downstream genes, we integrated ChIP-seq and RNA-seq analyses, investigating molecular mechanisms driving the response to OGD in this model.

Results

OGD stimulation increased cell apoptosis and induced time-dependent changes in the expression patterns of neurons, astrocytes, microglia, and oligodendrocytes in organotypic spinal cord slices, accompanied by a significant reduction in H3K27ac levels. Integrated ChIP-seq and RNA-seq analyses revealed that H3K27ac downregulation under hypoxic and ischemic conditions contributes to spinal cord damage by promoting neuroinflammation and disrupting gene regulation. Furthermore, we identified key downstream targets, including Apoc1, Spp1, Aff1, Brd4, KCNN3, and Rgma, which may represent promising therapeutic targets for SCI.

Conclusion

Our data underscore the pivotal role of H3K27ac in the organotypic spinal cord slice culture model following OGD exposure, offering promising avenues for neuroprotective therapies via epigenetic-immune regulation.

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H3K27乙酰化在氧-葡萄糖剥夺诱导的脊髓损伤中的作用及神经保护治疗的潜力。

目的：脊髓损伤（SCI）是一种使人衰弱的疾病，经常导致瘫痪和终身医疗挑战。研究表明，表观遗传修饰，特别是组蛋白乙酰化，在脊髓损伤缺氧缺血性事件后的神经保护中发挥作用。本研究的目的是探讨组蛋白H3K27乙酰化对脊髓损伤缺氧缺血耐受的影响及其潜在机制。方法：采用缺氧-葡萄糖剥夺（OGD）的器官型脊髓切片培养模型。我们评估了在这些条件下细胞凋亡和细胞类型模式的变化。缺氧和缺血后，我们分析了H3K27ac在不同神经细胞类型中的表达和分布。为了确定关键的下游基因，我们整合了ChIP-seq和RNA-seq分析，研究了该模型中驱动OGD反应的分子机制。结果：OGD刺激增加了细胞凋亡，诱导了器官型脊髓切片中神经元、星形胶质细胞、小胶质细胞和少突胶质细胞表达模式的时间依赖性变化，同时H3K27ac水平显著降低。ChIP-seq和RNA-seq综合分析显示，缺氧和缺血条件下H3K27ac下调通过促进神经炎症和破坏基因调控而导致脊髓损伤。此外，我们确定了关键的下游靶点，包括Apoc1、Spp1、Aff1、Brd4、KCNN3和Rgma，这些靶点可能是脊髓损伤有希望的治疗靶点。结论：我们的数据强调了H3K27ac在OGD暴露后的器官型脊髓切片培养模型中的关键作用，为通过表观遗传-免疫调节的神经保护治疗提供了有希望的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.